Lineage-specific signaling and targeting of PI3K gamma in myeloid malignancies

Active Project Grant Awarded Last action

Award ID
R01CA266389
Recipient
Awarding agency
Obligated
$5,136,187

Award facts

Assistance listing
93.396 Cancer Biology Research
Completion date 95% complete
Place of performance
Durham, NC 27705, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Myeloid malignancies are a group of often lethal cancers that derive from cells of the myeloid lineage of the hematopoietic system and include acute myeloid leukemia (AML) and diverse myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), the latter of which include chronic myelogenous leukemia (CML) and primary myelofibrosis. AML, the most common acute leukemia in adults, is responsible for significant cancer-related mortality, with a five-year survival rate of 28.9%. Although recent advances in genomics and other areas have significantly improved our understanding of the molecular events that underlie AML pathogenesis, these advances have yet to translate to significant improvements in the overall outcomes of patients with the disease, which have remained relatively unchanged over the last 40 years. In notable contrast to the scenario for AML, outcomes in patients diagnosed with a different leukemia, chronic lymphocytic leukemia (CLL), have been transformed in recent decades by drugs that target proteins such as bruton's tyrosine kinase (BTK), PI3KD, and CD20, whose expression and function are unique to the B cell lineage from which these cancers arise. These agents, which exhibit narrow side effect profiles, can thus be used chronically, alone or in combination with one another or additional agents to yield very long term disease control. Similar advances in the targeting of proteins with lineage-specific expression profiles and dependencies have led to substantial improvements in the treatment of patients with breast, prostate, and neural crest-derived tumors. Recently, we discovered that the PI3KG holoenzyme, comprised of the catalytic P110G and regulatory P101 subunits, is a profound regulator of AKT signaling, survival, and chemosensitivity in AML whose expression is restricted to hematopoietic cells, and particularly those of the myeloid lineage. Thus, targeting this critical signaling node leads to marked antitumor effects in AML cell lines, patient-derived cultures, and PDX models without the systemic toxicities historically associated with pan- or a/B isoform-specific PI3K inhibition. In this proposal, we describe studies to comprehensively characterize the expression and function of PI3KG across all major AML subtypes as well the normal cell types of the hematopoietic system. Further, we propose to define the fundamental mechanisms governing PI3KG expression in AML, then evaluate the therapeutic efficacy and safety of targeting this signaling axis in gold standard xenograft, humanized mouse, and genetically engineered mouse models of AML. Together, these studies will define a novel, lineage-restricted signaling axis regulating survival in myeloid malignancies whose selective targeting may add substantially to the therapeutic armamentarium in AML.

Transactions

Action Obligated Date
Amendment $8,791
Amendment $32,069
Amendment $79,121
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Amendment $288,648
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Amendment -$47,166
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Amendment $367,515
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Amendment $366,754
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Amendment $402,262
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Original award $422,717
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Subawards

Subrecipient Amount Awarded
Institut National De La Sante Et De La Recherche Medicale This proposal is thereby divided into three Aims, two of which will leverage the Puissant lab's unique expertise in the use of primary patient material and both… $439,912

Quick answers

Who received award R01CA266389?

R01CA266389 was awarded to Duke University by National Cancer Institute (National Institutes of Health) on April 1, 2022.

How much is award R01CA266389 worth?

$5,136,187 has been obligated on R01CA266389.

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